Principles of Flow Chemistry

Overview What is flow chemistry? Flow Chemistry vs Batch Chemistry Key principles of Flow Chemistry Residence Time Mixing Pressure Temperature Types of Flow Chemistry Summary

~1950 ~1920 ~1750 Labs in the past! New labs – same equipment Focus has been on new reactions, new chemistries. New equipment only designed to solve “non-reaction” steps: Flash chromatography Evaporation Reactor automation ~1920 ~1750 If you went back to your life in 1750, everything would be completely different. However, if you went into a lab in 1750, you could probably do the same.

A C B What is flow chemistry? In flow chemistry, reagents are continuously pumped through the reactor and the product is continuously collected. A C B

Batch and flow Classic way to do chemistry. Reagent A Reaction Mixture ~100µm Reagent B Reaction Mixture >5mm Reagent A Reagent B Classic way to do chemistry. Reagents are loaded into the reactor, mixed and left to react. The products is collected at the end, after the reaction has been completed and worked-up. . New technique. Reagents streams are continuously pumped into the flow reactor. Reagents mix and react in the flow reactor. The product leaves the reactor as a continuous stream. Key factors: Concentration Mixing Temperature Reaction time Key factors: Residence time (flow rates) Mixing Pressure Temperature

Key Principles of Flow Chemistry Residence Time Mixing Pressure Temperature

Residence Time = Reactor Volume / Flow Rate It can be defined as the time that every fraction of the reaction volume spends in the reactor Residence time is equivalent to reaction time in batch chemistry. It is calculated as follows: Two ways of controlling the residence time: Vary the reactor volume. Vary the flow rates. Example: to achieve a longer residence time, it is possible to either pump more slowly and/or use a reactor with a larger volume. Residence Time = Reactor Volume / Flow Rate

Worked example: Residence time Residence Time = Reactor Volume / Flow Rate Example: 2 reagents flowing into a 1 mL glass microreactor at 0.25 mL/min flow rate each. What is the residence time? To change the residence time to 8 min. What are the two options? Combined flow rate = 0.25 + 0.25 = 0.5 mL/min Residence time = 1/0.5 = 2 min Slow flow rates to 0.0625 mL/min each. Increase the reactor volume to 4 mL.

Mixing In batch chemistry, mixing is turbulent In flow chemistry, the mixing can be turbulent or laminar Small tube diameter results in laminar flow conditions (Reynolds number Re<2500) Radial diffusion

Mixing In turbulent flow conditions, static mixers are used to increase mass transfer In laminar flow conditions, mixing occurs by diffusion Diffusion time is proportional to distance squared, therefore over short distances, diffusion is rapid Reservoir Pump

Pressure In a flow reactor the total pressure at any location is made up of two factors: Back pressure due to flow This increases with higher flow rate, narrower channels or more viscous liquid Back pressure intentionally applied This is typically applied by a pressure regulator near the exit of the system Bubbles are best avoided as they can “push out” the reaction, thus lowering the residence time Flow reactors can be easily pressurised (much easier than a batch reaction) This can be useful for a variety of reasons: Reactions with gas Avoiding cavitation Superheating

Temperature Due to a higher surface area:volume ratio, flow reactors enable better heat transfer and therefore better temperature control Reactions cool down or heat up extremely rapidly (faster than a microwave) By pressurising, flow reactors can operate at temperatures above the typical boiling point of reactions This enables easy superheating of reactions e.g. 100ºC to 150ºC above reflux temperatures at atmospheric pressure

Different types of flow chemistry Homogeneous flow chemistry: Monophasic liquid-liquid reactions Biphasic liquid-liquid reactions (link to video) Two-phase microfluidic flows, Chemical Engineering Science 66 (2011) 1394 Heterogeneous flow chemistry: Solid-liquid reactions Gas-liquid reactions Gas-solid-liquid reactions

Liquid-Liquid Interactions Batch Flow Scaling   Surface Area Gravity   Surface Tension Emulsion Flow Chemistry is ideal for biphasic liquid reactions Flow Chemistry is very suitable for aqueous work-up

Microfluidic Method of Droplet Production Hydrophilic coating Hydrophobic OR Fluorophilic coating + + Hydrophilic surface Hydrophobic surface

Solids Solids in flow reactors can in some instances cause problems such as blockages The ability for flow reactors to tolerate solids varies greatly Higher ratio between channel diameter and particle size, the lower probability of a blockage Other factors such as the nature of the particle, reactor design and velocity of the reaction can all influence the likelihood of a blockage The use of solid reagents is typically easiest by isolating them in a “column” and flowing the reaction in solution through the packed column Solution to solids issues is often a chemistry solution (and not a technology solution): Adapt the chemistry Add co-solvents to increase solubility of products Reduce concentrations of reaction Examples of solids produced in Syrris flow chemistry systems (link to Asia Nanoparticle video):

What is the potential of flow chemistry?

Prof. Steve Ley’s paper 7 flow steps Mix of homogeneous and heterogeneous reactions including gas phase Synthesis, evaporation and workup all in flow Overall yield 40%

Examples of Syrris flow Chemistry Homogeneous catalysis Suzuki reaction Heck reaction Grubbs ring forming Multicomponent reactions Passerini 3CR Biginelli 3CR Ugi 4CR Deprotection chemistry BOC deprotection MOM deprotection and intra epoxide opening Ester saponification Ring formations Grubbs ring forming Ugi followed by ring closure to benzimidazole Diels Alder 1,3,4 Oxadiazole formation Fischer indole synthesis 1,3 Thiazole formation Pyrazole formation Oxidations and reductions Borohydride reduction Borane reduction of a heterocycle Reductive amination Dess Martin alcohol oxidation General Synthesis Aldol reaction Biphasic Schotten-Baumann HBTU amide coupling Elimination of an alcohol to alkene Esterification of an alcohol Wittig reaction Nucleophilic aromatic substitution SN1 reaction Mitsunobu reaction N-Alkylation

Residence Time = Reactor Volume / Combined Flow Rate Summary Flow chemistry is an exciting new tool for chemists. Reaction conditions: flow rates ratio, residence time, temperature. Variable parameters: flow rates, reactor volume, temperature The technology is growing fast. Later today you get a chance to see/use the most advanced flow chemistry systems available. Residence Time = Reactor Volume / Combined Flow Rate

Any questions?